The cellular responses controlled by the secreted Wnt proteins are essential to almost all aspects of embryogenesis. In developed tissue, genetic and molecular alterations that give rise to misactivation of these signaling processes frequently drive cancerous cell growth. We have identified two distinct chemical strategies to disable Wnt-mediated signaling from screening a large synthetic chemical library in cultured cells. Whereas one compound class targets an acyltransferase essential for the production of Wnt molecules, another class promotes the destruction of a linchpin transcriptional co- activator. The cell growth inhibitory effect of disabling Wnt-mediated signaling in certain cancerous contexts is well established. Yet, the ability of chemically based strategies to achieve similar effects is largely untested. The studies in this proposal will interrogate Wnt-mediated signaling at the molecular, cellular, and organismal level using new chemical biology-based tools, and establish a framework for the deployment of Wnt inhibitors in cancerous contexts. In particular, we focus on lung cancer given the dependence of this disease on both targets of our compound portfolio. These studies should facilitate a transition from front-line anti-cancer agents that are generally toxic to rapidly diving cells to those that are tailored to the underlying genetics of individual cancers.